1. GENETIC BASIS OF DISEASE- part 2

2. Genetic basis of disease part 2 objectives a. Define inborn errors of metabolism b. Describe the common characteristic features of inborn errors of metabolism. c. Correlate the patho physiological basis of prototypical and common inborn errors of metabolism with biochemical abnormalities. 2

3. Inborn Errors of Metabolism- IEM Introduction Inherited Metabolic Diseases Also called, Inherited Metabolic Diseases Congenital Metabolic Diseases or Congenital Metabolic Diseases Large group of genetic disorders, resulting in metabolic defects due to a genetically determined specific defects in a protein. single gene mutation ( IEM caused by a single gene mutation (reduced or absent gene), which leads defects in proteins result from to production or abnormal function. 3

4. 4 a. Define inborn errors of metabolism A groups of mainly Autosomal recessive diseases, sharing the following characteristic: 1. Occurs when both copies of genes are mutated. 2. Both sexes are affected equally. 3. Onset usually EARLY in life. 4. Frequently involved enzyme protein  Metabolic pathway block  Pathological consequences.

6. Common characteristic features of IEM Inheritance of Inborn Errors of Metabolism 1. Inheritance of Inborn Errors of Metabolism Most of the inborn errors of metabolism are inherited as: Autosomal recessive. There are also X-linked, and mitochondrial inherited. A Few are inherited as Autosomal dominant. 2. Racial and ethnic groups- the incidence varies with predominance of certain inborn errors of metabolism within particular groups. Some of these diseases occur in large numbers in communities in which consanguinity is common.

7. 3.Defect in an enzyme or transport protein 3.Defect in an enzyme or transport protein, which results in a disruption in a metabolic pathway. may result in toxic accumulations of substrates before the disruption+ accumulations intermediates from alternative metabolic pathways. Onset usually EARLY in life : 4. Onset usually EARLY in life : Carbohydrate or protein metabolism=present in the neonatal period or early infancy and tend to be rapidly progressive. Fatty acid oxidation, glycogen storage, and lysosomal storage disorders less severe present later in infancy or childhood and tend to be episodic.

8. General Outcomes of Inborn Errors of Metabolism 1. Accumulation of a substrate or its metabolic derivatives that are harmful or may interfere with normal function of cells. (S) 2. Accumulation of intermediates from alternative metabolic pathways. (C) 3. Decreased ability to synthesize essential compounds (P)- Deficiency of products 4. Defects in energy production.

9. enzyme 1 ( absent or no function) enzyme 1 ( absent or no function) P P Enzyme 1 is absent or not functioning Enzyme 1 is absent or not functioning Reaction 1 is stopped Reaction 1 is stopped Reaction 2 is activated Reaction 2 is activated P is absent or decrease P is absent or decrease S & C are increased S & C are increased C Any one of these (S,C,P) may have pathological effects. Single Gene Mutation Single Gene Mutation (of gene for enzyme 1) Reaction 2 Reaction 1 s

10. How to diagnose Relevant history.  Age of presentation of disease.  Family History. Chrorinic villus biopsy Amniocentesis Prenatal Diagnosis: Chrorinic villus biopsy is carried out in the first trimester and Amniocentesis in the second trimester Biochemical screening –  Basic investigations : ()  Basic investigations : ( CHO, LIPID AND PROTEINS ) Confirmatory test  Metabolic tests. (HPLC, Tandem mass spectrometry)  Sequencing of the specific gene (molecular genetic techniques)- PCR, Karyotyping, etc.. Program for screening all newborns for certain metabolic disorders  Prevention: Program for screening all newborns for certain metabolic disorders 10

11. c. Correlate the patho-physiological basis of prototypical and common inborn errors of metabolism with biochemical abnormalities Example-PKU 11

12. 12 the patho-physiological basis of Phenylketonuria (PKU) IEM: Single gene defects result in abnormalities in the synthesis or catabolism of proteins, carbohydrates, fats, or complex molecules. PKU- Commonest inherited inborn error disease, specially Scandinavian descent  commonest cause of mental retardation. PKU- Single gene defects, Autosomal recessive- caused by lack of enzyme phenylalanine hydroxylase and consequent inability to metabolize phenylalanine. Homozygous variants of disease has severe lack of phenylalanine hydroxylase leading hyperphenylalaninemia. PKU- affected infants are normal at birth.

13. Normal Biochemical pathway for phenylalanine 50% of the dietary phenylalanine  Protein synthesis. 50% of the reminder  Tyrosine (precursor of melanin)

14. PKU-Biochemical abnormalities Phenylketonuria – mutant enzyme is usually phenylalanine hydroxylase(E*) synthesize less tyrosine (often fair skinned), have  plasma levels of (Phe), excrete  phenylpyruvate and metabolites Increased phenylalanine (Phe)  Decreased tyrosine Block  Increased phenylpyruvic acid *E*

15. PKU-Biochemical abnormalities Phenylketonuria – Increase plasma levels of phenylalanine and its metabolites: 1. Induces brain damage. 2. Lack of tyrosine, (precursor of melanin), is responsible for light color of hair and skin (Hypopigementation). 3. I ncrease plasma level of phenylalanine Lead to excretion in large amount in urine and sweat- give strong mousy odor.

16. Clinical features of PKU. PKU – raised Plasma level of phenylalanine& its metabolites in early life if untreated;  - Impaired brain development  - Severe mental retardation (after 6 months)& low IQ.  - Neurological deficit- unable to walk and 2/3 can’t talk.  - Seizures + strong mousy odor in urine& sweat of infants.  - Tyrosine levels  deficiency of melanin formation --- decreased pigmentation (hypopigmentation) in hair & eyes. These complications can be delayed by:  Restriction of diet phenylalanine early in life.  Several screening procedures in antenatal and immediate in postnatal period. 16